Nobiletin alleviates UV-induced skin photodamage through protein kinase B-dependent mitochondrial protection and suppression of mitogen-activated protein kinase signaling.

BACKGROUND: UV radiation is a primary cause of skin photodamage and photoaging. Nobiletin (NOB), a Citrus originated polymethoxyflavone, exerts cytoprotective activities. However, the mechanism of NOB in mitigating UV‑induced skin injury has yet to be fully elucidated. METHODS: Herein, in vitro human keratinocytes, dermal fibroblasts, and in vivo mouse UV photodamage models were established to explore the photoprotective efficacy of NOB. Oxidative stress, mitochondrial function, apoptosis, histopathology, and involved signaling pathway were assessed. Network pharmacology, molecular docking, molecular dynamics, surface plasmon resonance, cellular thermal shift assay, and pathway inhibitor were used to identify and validate the underlying target and pathway. RESULTS: Low-dose NOB markedly alleviated UV-induced cytotoxicity, inflammatory responses and wound healing defects. It reversed redox imbalance, restored mitochondrial structure and dynamic homeostasis, and suppressed intrinsic apoptosis. Mechanistically, NOB bound to protein kinase B (AKT) to restore phosphatidylinositol 3-kinase (PI3K)-AKT and reduced epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) activation. In vivo experiments confirmed that topical NOB ameliorated UV-induced skin pathological damage, inflammation and mitochondrial dysfunction, while AKT blockade largely abolished its protective effects. CONCLUSION: This study demonstrates that NOB alleviates UV-induced photodamage through AKT-dependent mitochondrial protection and MAPK pathway suppression, providing novel mechanistic insights and a potential natural therapeutic candidate for UV-induced skin photodamage prevention and treatment.